Identification of new disease-causing genes in hereditary spastic paraplegia

Strumpell disease, also known as hereditary spastic paraplegia (HSP), represents a heterogeneous group of neurodegenerative disorders characterized by a progressive spasticity and weakness of the lower limbs. The disease is classified in "pure" and "complicated" forms on the basis of additional features associated with spasticity. Genetically, the disease has been reported to be autosomal dominant (AD), autosomal recessive (AR), or more rarely X-linked, but isolated cases are often seen in clinical practice. AD forms of HSP (ADHSP) are the most frequent in Western countries, but AR forms of HSP (ARHSP) are common in the Mediterranean basin. Roughly 50 HSP genes, denoted spastic gait genes (SPG), have been localized (mapping of the locus), and about 20 of them have been identified explaining approximately 40-60% of autosomal forms. The overall aim of this project is to study, clinically and genetically, families with HSP, to gain insight into the spectrum of gene mutations, their relative frequency, the associated clinical manifestations, and to use new and more traditional molecular genetic strategies to identify pathogenic mutations in new SPG. Identification of new HSP genes opens the possibility to study their putative functions, an essential prerequisite to develop innovative therapeutic approaches.