Long-term course and mutational spectrum of spatacsin-linked spastic paraplegia.
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.
Hehr
Ute
U
Department of Human Genetics, University of Regensburg, Regensburg, Germany.
Bauer
Peter
P
Winner
Beate
B
Schule
Rebecca
R
Olmez
Akguen
A
Koehler
Wolfgang
W
Uyanik
Goekhan
G
Engel
Anna
A
Lenz
Daniela
D
Seibel
Andrea
A
Hehr
Andreas
A
Ploetz
Sonja
S
Gamez
Josep
J
Rolfs
Arndt
A
Weis
Joachim
J
Ringer
Thomas M
TM
Bonin
Michael
M
Schuierer
Gerhard
G
Marienhagen
Joerg
J
Bogdahn
Ulrich
U
Weber
Bernhard H F
BH
Topaloglu
Haluk
H
Schols
Ludger
L
Riess
Olaf
O
Winkler
Juergen
J
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
D018389:Codon, Nonsense; D011506:Proteins; C520412:SPG11 protein, human