Hereditary spastic paraplegia 3A associated with axonal neuropathy

Neviana Ivanova, Kristl G. Claeys*, Tine Deconinck, Ivan Litvinenko, Albena Jordanova, Michaela Auer-Grumbach, Jana Haberlova, Ann Löfgren, Gisele Smeyers, Eva Nelis, Rudy Mercelis, Barbara Plecko, Josef Priller, Josef Zámečník, Berten Ceulemans, Anne Kjersti Erichsen, Erik Björck, Garth Nicholson, Michael W. Sereda, Pavel SeemanIvo Kremensky, Vanio Mitev, Peter De Jonghe

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

42 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)706-713
Number of pages8
JournalArchives of Neurology
Issue number5
Publication statusPublished - May 2007
Externally publishedYes


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