title: Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.
abstract: OBJECTIVE
  Hereditary 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.
  
  
  METHODS
  Neurological examination, cerebral magnetic resonance imaging (MRI), 18fluorodeoxyglucose positron emission tomography (PET), nerve biopsy, linkage and mutation analysis are presented.
  
  
  RESULTS
  Spastic 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.
  
  
  CONCLUSIONS
  We 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.
authors: Department of Human Genetics, University of Regensburg, Regensburg, Germany.
authors: Ute
authors: U
authors: Hehr
authors: Peter
authors: P
authors: Bauer
authors: Beate
authors: B
authors: Winner
authors: Rebecca
authors: R
authors: Schule
authors: Akguen
authors: A
authors: Olmez
authors: Wolfgang
authors: W
authors: Koehler
authors: Goekhan
authors: G
authors: Uyanik
authors: Anna
authors: A
authors: Engel
authors: Daniela
authors: D
authors: Lenz
authors: Andrea
authors: A
authors: Seibel
authors: Andreas
authors: A
authors: Hehr
authors: Sonja
authors: S
authors: Ploetz
authors: Josep
authors: J
authors: Gamez
authors: Arndt
authors: A
authors: Rolfs
authors: Joachim
authors: J
authors: Weis
authors: Thomas M
authors: TM
authors: Ringer
authors: Michael
authors: M
authors: Bonin
authors: Gerhard
authors: G
authors: Schuierer
authors: Joerg
authors: J
authors: Marienhagen
authors: Ulrich
authors: U
authors: Bogdahn
authors: Bernhard H F
authors: BH
authors: Weber
authors: Haluk
authors: H
authors: Topaloglu
authors: Ludger
authors: L
authors: Schols
authors: Olaf
authors: O
authors: Riess
authors: Juergen
authors: J
authors: Winkler
mesh_terms: D000328:Adult; D001921:Brain / Q000473:pathology; D002540:Cerebral Cortex / Q000000981:diagnostic imaging / Q000378:metabolism; D018389:Codon, Nonsense; D003071:Cognition; D003337:Corpus Callosum / Q000473:pathology; D005260:Female; D016368:Frameshift Mutation; D005808:Genes, Recessive; D006801:Humans; D008137:Longitudinal Studies; D009154:Mutation; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology; D010375:Pedigree; D049268:Positron-Emission Tomography; D011506:Proteins / Q000235:genetics*; D012720:Severity of Illness Index; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D013497:Sural Nerve / Q000473:pathology; D013788:Thalamus / Q000000981:diagnostic imaging / Q000378:metabolism; D016138:Walking
chemical_list: D018389:Codon, Nonsense; D011506:Proteins; C520412:SPG11 protein, human