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 Zámecník, Berten Ceulemans, Anne Kjersti Erichsen, Erik Björck, Garth Nicholson, Michael W Sereda, Pavel SeemanIvo Kremensky, Vanio Mitev, Peter De Jonghe

Research output: Contribution to journalArticlepeer-review

Abstract

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)706-13
Number of pages8
JournalArchives of Neurology
Volume64
Issue number5
DOIs
Publication statusPublished - May 2007

Keywords

  • Adolescent
  • Adult
  • Age of Onset
  • Aged
  • Amides
  • Aminobutyrates
  • Butyrates
  • Child
  • Cohort Studies
  • DNA Mutational Analysis
  • Family Health
  • Female
  • Genetic Predisposition to Disease
  • Humans
  • Male
  • Membrane Proteins
  • Middle Aged
  • Mutation
  • Polyneuropathies
  • Spastic Paraplegia, Hereditary
  • Vesicular Transport Proteins
  • Journal Article
  • Research Support, Non-U.S. Gov't

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