Hereditary spastic paraplegia 3A associated with axonal neuropathy.

OBJECTIVE To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia. DESIGN We screened a large cohort of 182 families and isolated cases with pure or complex hereditary spastic paraplegia phenotypes, which were negative for mutations in SPG4. RESULTS In 12 probands (6.6%), we identified 12 different SPG3A mutations (11 missense and 1 insertion/frameshift) of which 7 were novel and 3 were de novo. We found incomplete penetrance in 1 family (G482V). In most cases, SPG3A mutations were associated with an early age at onset (mean, 3 y); however, in 1 family (R495W mutation), symptoms started later (mean, 14 y) with clear intrafamilial variability (8-28 y). Six patients with an SPG3A mutation (F151S, Q191R, M408T, G469A, R495W) originating from 5 unrelated families presented with a complex form of hereditary spastic paraplegia associated with a neuropathy (17%). Our electrophysiological and pathological findings confirmed an axonal sensory-motor neuropathy. There was no correlation between the genotype and the presence of a neuropathy. CONCLUSIONS We conclude that mutations in SPG3A represent an important cause of patients in the overall hereditary spastic paraplegia population. SPG3A is more often associated with a neuropathy than previously assumed. Therefore, patients with a bipyramidal syndrome and a neuropathy should be screened for mutations in SPG3A.

[1]  M. Ruberg,et al.  A founder effect and mutational hot spots may contribute to the most frequent mutations in the SPG3A gene , 2006, Neurogenetics.

[2]  J. Fink,et al.  De novo occurrence of novel SPG3A/atlastin mutation presenting as cerebral palsy. , 2006, Archives of neurology.

[3]  M. Ruberg,et al.  SPG3A is the most frequent cause of hereditary spastic paraplegia with onset before age 10 years , 2006, Neurology.

[4]  L. Santoro,et al.  The R495W mutation in SPG3A causes spastic paraplegia associated with axonal neuropathy , 2005, Journal of Neurology.

[5]  M. Ruberg,et al.  Atlastin1 mutations are frequent in young-onset autosomal dominant spastic paraplegia. , 2004, Archives of neurology.

[6]  J. Weissenbach,et al.  Early onset autosomal dominant spastic paraplegia caused by novel mutations in SPG3A , 2004, Neurogenetics.

[7]  E. Bertini,et al.  Incomplete penetrance in an SPG3A-linked family with a new mutation in the atlastin gene , 2004, Neurology.

[8]  W. Engel,et al.  Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus , 2004, Human mutation.

[9]  A. Crosby,et al.  SPG3A mutation screening in English families with early onset autosomal dominant hereditary spastic paraplegia , 2003, Journal of the Neurological Sciences.

[10]  J. Fink.  Advances in the hereditary spastic paraplegias , 2003, Experimental Neurology.

[11]  A. Tessa,et al.  SPG3A: An additional family carrying a new atlastin mutation , 2002, Neurology.

[12]  P. Hedera,et al.  Mutations in a newly identified GTPase gene cause autosomal dominant hereditary spastic paraplegia , 2001, Nature Genetics.

[13]  S. Antonarakis,et al.  Nomenclature for the description of human sequence variations , 2001, Human Genetics.