Hereditary spastic paraparesis in Austria

Hereditary spastic paraparesis (HSP) is a heterogeneous group of neurodegenerative disorders characterized by slowly progressive spasticity of the lower extremities with an estimated prevalence of 2.0 - 9.6 / 100000. Based on the clinical presentation HSP can be subdivided into two main types, the pure and the complicated forms, depending on the absence or presence of additional neurological or non-neurological features. Recent molecular genetic studies have demonstrated that both pure and complicated HSP are genetically highly heterogeneous. To date, at least 15 genetic subtypes have been mapped of which seven are responsible for autosomal dominant pure HSP. In the chromosome 2p linked type, which accounts for the majority of autosomal dominant HSP, the gene (Spastin) has recently been identified. In this research project we aim to perform clinical, electrophysiological, MRI and molecular genetic studies in HSP patients and families from the Southeast of Austria. In the first step mutation screening in the spastin gene will be performed. Then, families which have been excluded for mutations within this gene will undergo molecular genetic studies to confirm or exclude linkage to the known HSP loci. If there is evidence of linkage to one of the known loci, complete haplotypes will be constructed by marker saturation with the attempt of refining the extent of the critical region based on the occasional presence of recombinants. Our studies are the first intention to perform molecular genetic testing of HSP in Austria and aim to determine the frequency of different genetic subtypes of HSP in the Southeast of Austria. Furthermore, they enable phenotype- genotype correlation studies to estimate the phenotypic variation of the disease. The possibility of genetic testing in patients with HSP is of critical importance for patients, clinicians, and geneticists and will be the gold standard diagnostic procedure in near future. The knowledge of the disease causing gene facilitates diagnosis and differential diagnosis in sporadic cases, enables accurate family counselling and provides the possibility of prenatal diagnosis in severe cases.

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 on the clinical presentation HSP can be subdivided into two main types, the pure and the complicated forms, depending on 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. Within the past two years the present research project enabled us to perform clinical, electrophysiological and molecular genetic studies in patients and families with different forms of HSP in the Austrian population. We detected several mutations in the spastin (SPG4) and the atlastin (SPG3) genes in families with pure and complicated HSP. SPG4 and SPG3 represent the most common forms of autosomal dominant HSP. One large family was excluded for all known autosomal dominant HSP loci. We also recruited four families with SS and detected clinical similarities of SS and distal hereditary motor neuropathy (dHMN). Based on our molecular genetic studies we were able to refine the SS locus on chromosome 11q12-q14. Finally, we demonstrated that heterozygous 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. Mutations in the BSCL2 genes represent a common cause of dHMN and SS in Austria. A collaboration study also confirmed BSCL2 mutations in other families with dHMN and Silver syndrome; originating from England, Italy, Germany, Belgium and Brazil. 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 prenatal diagnosis as sometimes desired in severe early-onset cases. This HSP research project enabled us to introduce molecular genetic testing in Austria in almost all forms HSPs.