title: Hereditary spastic paraplegia 3A associated with axonal neuropathy.
abstract: OBJECTIVE
  To study the frequency and distribution of mutations in SPG3A in a large cohort of patients with hereditary spastic paraplegia.
  
  
  METHODS
  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.
authors.affiliation: Laboratory of Molecular Pathology, Sofia Medical University, Sofia, Bulgaria.
authors.forename: Neviana
authors.initials: N
authors.lastname: Ivanova
authors.forename: Kristl G
authors.initials: KG
authors.lastname: Claeys
authors.forename: Tine
authors.initials: T
authors.lastname: Deconinck
authors.forename: Ivan
authors.initials: I
authors.lastname: Litvinenko
authors.forename: Albena
authors.initials: A
authors.lastname: Jordanova
authors.forename: Michaela
authors.initials: M
authors.lastname: Auer-Grumbach
authors.forename: Jana
authors.initials: J
authors.lastname: Haberlova
authors.forename: Ann
authors.initials: A
authors.lastname: Löfgren
authors.forename: Gisele
authors.initials: G
authors.lastname: Smeyers
authors.forename: Eva
authors.initials: E
authors.lastname: Nelis
authors.forename: Rudy
authors.initials: R
authors.lastname: Mercelis
authors.forename: Barbara
authors.initials: B
authors.lastname: Plecko
authors.forename: Josef
authors.initials: J
authors.lastname: Priller
authors.forename: Josef
authors.initials: J
authors.lastname: Zámecník
authors.forename: Berten
authors.initials: B
authors.lastname: Ceulemans
authors.forename: Anne Kjersti
authors.initials: AK
authors.lastname: Erichsen
authors.forename: Erik
authors.initials: E
authors.lastname: Björck
authors.forename: Garth
authors.initials: G
authors.lastname: Nicholson
authors.forename: Michael W
authors.initials: MW
authors.lastname: Sereda
authors.forename: Pavel
authors.initials: P
authors.lastname: Seeman
authors.forename: Ivo
authors.initials: I
authors.lastname: Kremensky
authors.forename: Vanio
authors.initials: V
authors.lastname: Mitev
authors.forename: Peter
authors.initials: P
authors.lastname: De Jonghe
mesh_terms: D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D000577:Amides; D000613:Aminobutyrates; D002087:Butyrates; D002648:Child; D015331:Cohort Studies; D004252:DNA Mutational Analysis; D005192:Family Health; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D008875:Middle Aged; D009154:Mutation; D011115:Polyneuropathies / Q000150:complications / Q000235:genetics* / Q000473:pathology; D015419:Spastic Paraplegia, Hereditary / Q000150:complications / Q000235:genetics* / Q000473:pathology; D033921:Vesicular Transport Proteins / Q000235:genetics*
chemical_list: C488113:4-((2-oxohexadecanoyl)amino)butanoic acid; D000577:Amides; D000613:Aminobutyrates; D002087:Butyrates; D008565:Membrane Proteins; D033921:Vesicular Transport Proteins; C513390:ZFYVE27 protein, human