Hereditary spastic paraplegias (HSP) are a group of clinically and genetically heterogeneous diseases which mainly affect the corticospinal tracts. They result in a functional gait handicap often associated to various other neurological symptoms. Very few symptomatic treatments exist against those disabling diseases which often lead to the social isolation of the patients and their families. Improving this situation first requires to decipher the genetic basis of the clinical heterogeneity of HSP, and to provide a sharp phenotypic description of each genetic entity. To this aim, we propose to associate four specialized clinical and research teams from Paris, Tübingen, Rome and Jerusalem and combine their biological resources, manpower, knowledge and expertise gained within two recognized networks, SPATAX and GeNeMove, devoted respectively to spinocerebellar degenerations and movement disorders. The added value of this association will come from its only focus on HSP and its extended geographical coverage with about 1300 recruited families with HSP from Europe, North Africa and Middle East. This represents the largest known collection worldwide.
We have therefore identified 5 aims that can reasonably be achieved within the duration of this project (1) the extension of this unique collection of HSP families to increase the coverage of all forms of HSP, including the rare ones; (2) the extension of the clinical and molecular spectrum of known HSP genes through genetic testing, that the development of a resequencing microarray by the Tübingen group will greatly enhance; (3) the identification of new loci in dominant (Tübingen) and recessive (Paris in collaboration with Rome and Jerusalem) HSP forms, and in recessive spastic ataxias (Rome), (4) the identification of several responsible genes, including SPG5 and SPG15, given our recent significant reduction of the candidate intervals and SAX2, SPG28, 30, 32, 36 and 37 that we recently localized and (5) the establishment of genotype-phenotype correlations in a large number of sampled families which will improve the nosology of these complex disorders.
The results of these studies will offer to more patients and their families the possibility of a molecular diagnosis and will open new avenues of research to understand the deleterious mechanisms involved in the pathology. Ultimately, patients will benefit from the gained pathophysiological knowledge, which will be translated into therapeutic approaches.