Heriditary spastic paraparesis in Austria

Hereditary spastic paraparesis (HSP), also called familial spastic paraparesis (FSP) is a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities. Based an the clinical presentation HSP can be subdivided into two main types, the pure and the complicated forms, depending an the absence or presence of additional neurological or non-neurological features. Silver syndrome (SS, SPG17) is a particularly disabling rare form of autosomal dominant complicated HSP in which spasticity of the lower limbs is accompanied by marked weakness and wasting of the small hand muscles. In the Aast years wie performed clinical, electrophysiological and molecular genetic studies in patients and families with different forms of HSP. We detected several mutations in the spastin and the atlastin genes in families with pure and complicated HSP. Wie also recruited four families with SS but also detected clinical similarities of SS and distal hereditary motor neuropathy (dHMN). Based an our molecular genetic studies we were able to refine the SS locus an chromosome l lg12-q14. Finally, we demonstrated that heterozygeous mutations in the Berardinelli Seip congenital lipodystrophy gene (BSCL2 gene) are associated with SS but also with some forms of dHMN establishing that both disorders are, in fact, phenotypic extremes of an entity sharing the Same genetic aetiology. This research project represents a succession of the first Austrian HSP project (FWF, P15378) and aims to recruit and analyze further HSP and also dHMN patients in order to define the prevalence of these disorders in Austria. The cloning of genes and the identification of mutations of different variants of the HSPs and dHMNs will permit insight into the causes of these disorders in the future. The identification of such genes has a major impact in the diagnosis and will provide new paradigms for functional studies. Furthermore, it enables more accurate genetic counseling and Arenatal diagnosis as sometimes desired in severe early-onset cases.

The above mentioned project started in June 2004 and ended on 31st; January 2006. Within the scope of the project patients and families with pure and complicated hereditary spastic paraparesis (HSP) have been recruited and examined both clinically and electrophysiologically. Blood samples were taken for DNA-analyses. Special attention was paid to patients from Styria, Upper and Lower Austria, Vienna, Salzburg and Carinthia. It could be shown that HSP is genetically heterogeneous in Austria. Mutations were found in the Spastin and Atlastin genes and a novel gene, BSCL2 (Berardinelli-Seip Congenital Lipodystrophy 2 gene), was identified (in part one of the Austrian HSP-project). In the course of this project, additional families and patients with dHMN-V and Silver Syndrome caused by mutations in BSCL2 from Austria and abroad have been recruited and examined. The diagnosis was genetically confirmed or excluded pointing to genetic heterogeneity of this disease. Ninety patients with dHMN-V or Silver Syndrome and the N88S mutation in BSCL2 were phenotypically and genotypically analyzed and these results were published in a highly ranked journal. Additionally, the GARS gene, which was recently published as a second cause of dHMN-V and CMT2D Syndrome, was included in the genetic analysis. Further 33 families with dHMN-V/CMT2D and Silver Syndrome, as well as 68 individuals with undefined phenotypical subtype of dHMN, who have only been analyzed according to a mutation in exon 3 of BSCL2, were evaluated. In the 33 patients and families four mutations in the BSCL2 gene and one new mutation in the GARS gene were identified. These results underline the exceptional genetic heterogeneity of this disease. This work was carried out in close collaboration with other institutions from Germany, England, Italy, Australia, Hungary, etc. The Austrian HSP-project (parts 1 and 2) initiated research and diagnostics in the field of hereditary spastic paraparesis in Austria. A new gene associated with a complicated form of the disease could be identified and important epidemiologic insights providing significant advantages for affected persons were gained.