• Ute Hehr, Peter Bauer, Beate Winner, Rebecca Schule, Akguen Olmez, Wolfgang Koehler, Goekhan Uyanik, Anna Engel, Daniela Lenz, Andrea Seibel, Andreas Hehr, Sonja Ploetz, Josep Gamez, Arndt Rolfs, Joachim Weis, Thomas M Ringer, Michael Bonin, Gerhard Schuierer, Joerg Marienhagen, Ulrich Bogdahn, Bernhard H F Weber, Haluk Topaloglu, Ludger Schols, Olaf Riess, and Juergen Winkler.
• Department of Human Genetics, University of Regensburg, Regensburg, Germany.
• Ann. Neurol. 2007 Dec 1;62(6):656-65.

ObjectiveHereditary spastic paraplegias (HSPs) comprise a heterogeneous group of neurodegenerative disorders resulting in progressive spasticity of the lower limbs. One form of autosomal recessive hereditary spastic paraplegia (ARHSP) with thin corpus callosum (TCC) was linked to chromosomal region 15q13-21 (SPG11) and associated with mutations in the spatacsin gene. We assessed the long-term course and the mutational spectrum of spatacsin-associated ARHSP with TCC.MethodsNeurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented.ResultsSpastic paraplegia in patients with spatacsin mutations (n = 20) developed during the second decade of life. The Spastic Paraplegia Rating Scale (SPRS) showed severely compromised walking between the second and third decades of life (mean SPRS score, >30). Impaired cognitive function was associated with severe atrophy of the frontoparietal cortex, TCC, and bilateral periventricular white matter lesions. Progressive cortical and thalamic hypometabolism in the 18fluorodeoxyglucose PET was observed. Sural nerve biopsy showed a loss of unmyelinated nerve fibers and accumulation of intraaxonal pleomorphic membranous material. Mutational analysis of spatacsin demonstrated six novel and one previously reported frameshift mutation and two novel nonsense mutations. Furthermore, we report the first two splice mutations to be associated with SPG11.InterpretationWe demonstrate that not only frameshift and nonsense mutations but also splice mutations result in SPG11. Mutations are distributed throughout the spatacsin gene and emerge as major cause for ARHSP with TCC associated with severe motor and cognitive impairment. The clinical phenotype and the ultrastructural analysis suggest a disturbed axonal transport of long projecting neurons.

37 keywords...

hide…