Aktuelle Neurologie 2007; 34 - P515
DOI: 10.1055/s-2007-987786

Spatacsin: a new gene for complicated hereditary spastic paraplegia

J Winkler 1, B Winner 1, P Bauer 1, R Schüle 1, W Köhler 1, G Uyanik 1, S Plötz 1, U Bogdahn 1, B Weber 1, A Oelmez 1, H Topaloglu 1, U Hehr 1, L Schöls 1, O Rieß 1
  • 1Regensburg, Tübingen, Wermsdorf; Ankara, TR

Aims: Hereditary spastic paraplegias (HSPs) comprise a clinically and genetically heterogeneous group of neurodegenerative disorders, resulting in progressive spasticity of the lower limbs. In contrast to “pure HSP“, additional clinical features are present in patients with complicated HSP. We have recently characterized in detail the phenotype of two German pedigrees with AR-HSP with thin corpus callosum (TCC; Winner et al. 2004 and 2006). For 4 large consanguineous Turkish families we could narrow down the SPG11 minimal critical region to a 2,93 cM interval with a maximum LOD score of 11,84 (Oelmez et al., 2006). Recently, KIAA1840 could be identified as the Spatacsin gene, associated with SPG11 (Stevanin et al., 2007).

Methods: Clinical examination, evaluation of brain MR images and linkage analysis of patients/families with suspected SPG11 phenotype (inclusion criteria: spastic paraplegia, cognitive decline, MRT: confirmed TCC). Sequence analysis of 24 candidate genes from the SPG11 locus.

Results: Each of the affected index patients fulfilled the criteria of AR-HSP with TCC. Two of the Turkish families with linkage to SPG11 were found to be homozygous for two different frameshift mutations in exon 17 of the Spatacsin gene. In the third Turkish family we identified a homozygous splice mutation in intron 2. One large pedigree from Saudi-Arabia was homozygous for a nonsense mutation in exon 10. Furthermore, one well characterized sporadic patient of German origin was heterozygous for a nonsense mutation in exon 2 and a splice mutation in intron 7. However, in one German phenotypic AR-HSP with TCC pedigree no mutation was present in the Spatacsin gene. First signs of spastic paraplegia in our patient cohort with Spatacsin mutations appeared in the second decade of life. Application of the spastic paraplegia rating scale (SPRS; Schüle et al., 2006) revealed severely compromised walking and stair climbing between 20 and 30 years of life (mean SPRS score >30). Progressive deterioration of cognitive functions was noted.

Conclusions: SPG11 is caused by truncating mutations of the human Spatacsin gene and emerged as one major cause of complicated AR-HSP with TCC. This is the first report for families of German, Turkish and Saudi-Arabien descent. More importantly, it reveals, that AR-HSP with TCC may also be associated with other gene loci than Spatacsin.