title: Detection of novel mutations and review of published data suggests that hereditary spastic paraplegia caused by spastin (SPAST) mutations is found more often in males.
abstract: BACKGROUND
  Hereditary spastic paraplegia (HSP) is characterised in its pure form by slowly progressive spastic paraparesis. Around 40% of autosomal dominant (AD) cases are caused by mutations in SPAST, encoding spastin.
  
  
  METHODS
  The clinical and investigation details of all patients with a SPAST mutation identified through our centre were reviewed. All published reports of SPAST mutations where the sex of patients was given were subsequently analysed in order to determine whether there is evidence of one sex being preferentially affected.
  
  
  RESULTS
  In total 22 probable pathogenic changes were detected, including 11 novel ones. One patient carried two adjacent missense mutations. The pathogenicity of a further novel missense mutation is uncertain. Most patients had a pure phenotype, although mild peripheral neuropathy was sometimes present. The total number of patients with SPAST mutations was 27, as three of the previously known mutations were present in more than one person. The excess of males over females in our population (17:10) prompted us to review all published studies where the sex of the patients was given (n=31). A significant excess of males was identified (ratio 1.29, p=0.0007).
  
  
  CONCLUSIONS
  Our results are consistent with data suggesting that SPAST mutations mostly cause a pure HSP phenotype. The excess of males in our sample and in published reports suggests that penetrance or severity may be sex-dependent, and merits further investigation as it may have important implications for counselling.
authors.affiliation: Department of Clinical Neurosciences, University College London Institute of Neurology, Royal Free Campus, London, NW3 2PF, UK. c.proukakis@medsch.ucl.ac.uk
authors.forename: Christos
authors.initials: C
authors.lastname: Proukakis
authors.forename: David
authors.initials: D
authors.lastname: Moore
authors.forename: Robyn
authors.initials: R
authors.lastname: Labrum
authors.forename: Nicholas W
authors.initials: NW
authors.lastname: Wood
authors.forename: Henry
authors.initials: H
authors.lastname: Houlden
mesh_terms: D000251:Adenosine Triphosphatases / Q000235:genetics*; D016208:Databases, Factual / Q000706:statistics & numerical data; D005091:Exons / Q000235:genetics; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D055106:Genome-Wide Association Study / Q000379:methods; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D015419:Spastic Paraplegia, Hereditary / Q000209:etiology* / Q000235:genetics*; D000074181:Spastin
chemical_list: D000251:Adenosine Triphosphatases; D000074181:Spastin; C400283:SPAST protein, human